Non-small cell lung cancer (NSCLC) makes up the vast majority of lung cancer cases and is a devastating diagnosis, with only a 15% chance of surviving 5 years. The greatest advance in the last decade has been the discovery that NSCLC tumors with identical histology diagnoses may have distinct genotypes, or genetic diagnoses;this is a unique opportunity to personalize cancer therapy. For example, patients with EGFR mutations in their tumors respond very well to EGFR inhibitors, with rapid, near complete reduction of their cancers that lasts, in some cases, for several years. Unfortunately tumors that initially respond to EGFR inhibitors eventually become resistant, with patients likely to die soon thereafter. The biology of acquired drug resistance is incompletely understood and is largely inferred from pre-clinical models. Therapies to circumvent possible resistance mechanisms are under study, but proof-of-concept will depend on the ability to give the experimental therapies to patients selected for a distinct mechanism of drug resistance. Most cancer clinical trials do not yet use this approach, since resistance-mechanism-specific diagnostics are not widely available. A fundamentally new translational research paradigm is therefore needed to gain insight into the problem of acquired drug resistance and design the next generation of targeted cancer therapies. Our project brings real- time, serial tumor biopsies to the clinic, in order to test for changing genotypes as resistance and sensitivity to targeted treatments changes over time. We aim to use the biopsied tumor samples to steer patients towards the most appropriate treatments and also study the material in the laboratory to learn more about acquired drug resistance. Ultimately, dynamic tumor genotyping will depend on non-invasive techniques to generate a safe and feasible "real world" method that spares patients from the risks of invasive tumor biopsies. We aim to study such a platform and will test an innovative device that can pluck rare cancer cells out of the blood circulation, allowing us to genotype them to compare with the actual tumor biopsies. Our project overall will improve our understanding of resistance to EGFR-targeted therapy and advance the next generation of treatment strategies and diagnostic methods. PUBLIC HEALTH RELEVANCE: Non-small cell lung cancer is a devastating diagnosis with a poor prognosis. A recent breakthrough is the discovery of gene mutations in EGFR that define a subroup of patients with great response to targeted therapy directed at EGFR. However, these drugs only works about a year before resistance emerges. Our project aims to understand how patients become resistant and how to personalize therapy after resistance.